CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion

Abstract

The aggressiveness of malignant melanoma is associated with differential expression of CXCL-8 and its receptors, CXCR1 and CXCR2. However, the precise functional role of these receptors in melanoma progression remains unclear. In this study, we investigate the precise functional role of CXCR1 and CXCR2 in melanoma progression. CXCR1 or CXCR2 were stably overexpressed in human melanoma cell lines, SBC-2 (non-tumourigenic) and A375P (low-tumourigenic) exhibiting low endogenous expression of receptors. Functional assays were performed to study the resulting changes in cell proliferation, motility and invasion, and in vivo tumour growth using a mouse xenograft model. Our data demonstrated that CXCR1-or CXCR2-overexpressing SBC-2 and A375P melanoma cells had enhanced proliferation, chemotaxis and invasiveness in vitro. Interestingly, CXCR1 or CXCR2 overexpression in SBC-2 cells induced tumourigenicity, and A375P cells significantly enhanced tumour growth as examined in vivo. Immunohistochemical analyses showed significantly increased tumour cell proliferation and microvessel density and reduced apoptosis in tumours generated from CXCR1-or CXCR2-overexpressing melanoma cells. CXCR1-or CXCR2-induced modulation of melanoma cell proliferation and migration was observed to be mediated through the activation of ERK1/2 phosphorylation.Together, these studies demonstrate that CXCR1 and CXCR2 play essential role in growth, survival, motility and invasion of human melanoma.

Chemokines in tumor development and progression

“…The same pathway is utilized to promote proliferation of esophageal cancer cells [21] and melanoma cells [22]. Accumulating evidence also implicates CXCR4 in the proliferation of various cancer cells including ovarian, glioma, melanoma, lung, renal, and thyroid cancer cells [23,24].…”

“…It is widely acknowledged that leukocytes are localized in both the tumor-supporting stroma and the tumor areas and might account for up to 50% of the tumor mass, the most predominant subset being macrophages [22,44].…”

“…Tumor-associated macrophages (TAMs) are derived mostly from circulating monocytes which are attracted into tumor sites, by locally produced chemotactic factors, such as CCL2, CCL5, CCL7, CCL8, CXCL12, and macrophage colony stimulating factor (M-CSF) [22].…”

“…Several lines of evidence indicate that CCL2 plays an important role in TAM recruitment among these chemotactic factors [22,44]. Combined treatment with azoxymethane and repeated dextran sodium sulfate solution ingestion causes the development of multiple tumors in murine colons, together with a massive infiltration of monocytes/macrophages expressing cyclooxygenase (COX)-2, an enzyme crucially involved in colon carcinogenesis [45].…”

Chemokines in cancer related inflammation

“…Most tumors express CXCR4 at levels higher than the normal corresponding tissues [30,74]; other investigated receptors are for instance: CCR6 and CX3CR1 in colorectal and pancreatic cancer [75,76], CXCR6 in prostate cancer [77], CXCR2 in melanoma [78], and esophageal cancer cells [77], CCR7 in squamous cell carcinoma of the head and neck [79] and CCR10 in melanoma [80]. In ovarian cancer cells, the small CXCR4 antagonist CTCE-9908 caused cells death via a mechanism that was not apoptotic but involved damage of DNA checkpoint proteins and cell cycle arrest [81].…”